JP5301665B2 - Pyrrolidin-3-ylmethyl-amine as an orexin antagonist - Google Patents

Abstract

The present invention is concerned with novel sulfonamides of formula I wherein R1, R2, Ar, Hetaryl, m and n are as described in the description and claims. The compounds are orexin receptor antagonists, useful in the treatment of disorders, in which orexin pathways are involved.

Description

  The present invention has the formula

［式中、
Ｒ^１は、ハロゲンであり；
Ｒ^２は、ハロゲン、低級アルキル、低級アルコキシ、ハロゲンにより置換された低級アルキル、ハロゲンにより置換された低級アルコキシ、又はフェニルであり；
ヘタリールは、

[Where:
R ¹ is halogen;
R ² is halogen, lower alkyl, lower alkoxy, lower alkyl substituted with halogen, lower alkoxy substituted with halogen, or phenyl;
Hetariru

（ＸはＯ又はＳである）であり；
Ａｒは、アリール又はヘテロアリールであり；
ｎは、０、１又は２であり；
ｍは、０、１又は２である］
で示される化合物又はその薬学的に適切な酸付加塩、光学的に純粋な鏡像異性体、ラセミ体若しくはジアステレオマー混合物に関する。

(X is O or S);
Ar is aryl or heteroaryl;
n is 0, 1 or 2;
m is 0, 1 or 2]
Or a pharmaceutically suitable acid addition salt, optically pure enantiomer, racemate or diastereomeric mixture thereof.

  The compounds of formula I are orexin receptor antagonists, and related compounds include sleep apnea, narcolepsy, insomnia, sleep parasomnia, jet lag syndrome, circadian rhythm disorder, restless leg syndrome, Sleep disorder, anxiety, depression, manic depression, obsessive compulsive disorder, affective neurosis, depressive neurosis, anxiety, mood disorder, delirium, panic attack disorder, post-traumatic stress disorder, sexual dysfunction, schizophrenia Psychosis, psychosis, cognitive impairment, Alzheimer's and Parkinson's disease, dementia, mental retardation, dyskinesia, such as Huntington's disease and Tourette syndrome, addiction, craving related to drug abuse, seizure disorders, epilepsy, Neurological and neurodegenerative disorders, metabolic diseases such as obesity, diabetes, anorexia including anorexia and bulimia, asthma, migraine, Pain, neuropathic pain, sleep disorders associated with psychiatric, neurological and neurodegenerative disorders, neuropathic pain, increased or worsened sensitivity to pain, eg hyperalgesia, causalgia, and allodynia, acute pain Burn pain, back pain, combined local pain syndrome I and II, joint pain, post-stroke pain, postoperative pain, neuralgia, HIV infection related pain, post-chemotherapy pain, irritable bowel syndrome and orexin systemic It has been found that it may be useful in the treatment of disorders involving the orexin pathway, such as other diseases associated with dysfunction.

The hypothalamic neuropeptide family orexin (hypocretin) plays an important role in the modulation of feeding behavior, energy homeostasis and sleep-wake cycle (Siegel, Annu. Rev. Psychol., 55, 125-148, 2004) . Orexin-A / hypocretin 1 (OX-A, amino acid 33 residues) and orexin-B / hypocretin 2 (OX-B, amino acid 28 residues) are the same due to proteolytic processing of 130 amino acid prepro-orexin Obtained from the precursor (de Lecea et al., Proc Natl Acad Sci USA, 95, 322-327, 1998; Sakurai T. et al., Cell, 92, 573-585, 1998). Orexin levels show diurnal variation that is highest during the activity cycle. Two receptor subtypes named orexin-1 receptor (OX ₁ R) and orexin-2 receptor (OX ₂ R) have been identified. From the characterization of both receptors in binding and functional assays, OX ₁ R is selective for OX-A while OX ₂ R is a non-selective receptor for both OX-A and OX-B; Conversely, OX-A is a non-selective neuropeptide that binds to OX ₁ R and OX ₂ R with similar affinity, while OX-B is selective and more responsive to OX ₂ R It has been demonstrated to have high affinity (Sakurai T. et al., Cell, 92, 573-585, 1998). Both receptors belong to the class A family of G protein-coupled receptors (GPCRs) that couple to activation of phospholipase C via Gq _{/ 11} , hydrolyzing phosphoinositide (PI) and increasing intracellular Ca ²⁺ levels. Lead. However, it has been shown that OX2R can also be coupled to the cAMP pathway via Gi _{/ o} (Sakurai, Regulatory Peptides, 126, 3-10, 2005). From Northern blot analysis of adult rat tissues, prepro-orexin mRNA is detected only from the brain (except in small amounts in the testis), and OX ₁ R and OX ₂ R transcripts are also detected only from the brain. (Sakurai T. et al., Cell, 92, 573-585, 1998). Similar results were obtained using a human multi-tissue Northern blot. Distribution studies in rat brain using in situ hybridization and immunohistochemistry showed that orexin neurons were found only in the lateral hypothalamic area and projected to the entire CNS (Peyron et al., J Neurosci , 18, 9996-10015, 1998; Nambu et al., Brain Res., 827, 243-60, 1999). In addition, both OX ₁ and OX ₂ receptors are present in brain regions important for sleep / wake regulation.

Based on the following lines of evidence, it has been suggested that the disrupted orexin system is responsible for narcolepsy: (a) Prepro-orexin knockout mice had a phenotype with characteristics remarkably similar to narcolepsy (Chemelli et al., Cell, 98, 437-451, 1999), (b) a mutation that disrupts the gene encoding OX ₂ R (canarc-1) was found to be responsible for canine narcolepsy (Lin et al., Cell, 98, 365-376, 1999), (c) lack of OX-A and OX-B was observed in human narcolepsy patients (Nishino et al., Lancet, 355, 39 -40, 2000; Peyron et al., Nature Medicine, 6, 991-997, 2000), (d) Modafinil, an anti-narcolepsy with unknown mechanism of action, has been shown to activate orexin neurons (Mignot et al., Sleep, 11, 1012-1020, 1997; Cheme lli et al, Cell, 98, 437-451, 1999). Intracerebroventricular (icv) administration of OX-A prolongs wakefulness and reduces total REM sleep by 84% in rats (Piper et al., Eur. J. Neuroscience, 12, 726-730). , 2000). Taken together, these observations are consistent with the important role the orexin system plays in regulating the sleep / wake cycle.

Orexin plays an important role in stress and anxiety through the interaction of orexin and the corticotropin releasing factor (CRF) system in the hypothalamus (Sakamoto et al., Regul Pept., 118, 183-91, 2004). Icv injection of OX-A induces grooming (stress response), which is partially blocked by CRF antagonists (Ida et al., Biochem. Biophys. Res. Comm., 270, 318-323, 2000 ). OX ₂ R is highly expressed in the adrenal medulla, while OX ₁ R is high in the adrenal cortex. Both OX-A and OX-B stimulate corticosterone release in plasma and induce c-Fos in the hypothalamic paraventricular nucleus (PVN) (Kuru et al., Neuroreport, 11, 1977). -1980, 2000). Furthermore, orexin neurons that project to CRF neurons mainly express OX ₂ R (Winsky-Sommerer et al., J. Neuroscience, 24, 11439-11448, 2004). Thus, stimulation of OX2R activates the hypothalamus / pituitary / adrenal cortex (HPA) system. Interestingly, in this connection, the increase in plasma ACTH induced by orexin A is a selective antagonist for OX-2R (N-{(1S) -1- (6,7-dimethoxy-3,4-dihydro -(1H) -isoquinolinyl) carbonyl} -2,2-dimethylpropyl) -N- {4-pyridinylmethyl} amine was reported to be weakened (Chang et al., Neurosci Res., 21 Dec 2006). A recent preclinical report (Suzuki et al., Brain Research, 1044, 116-121, 2005) suggested an anxiolytic effect of OX-A. Icv injection of OX-A caused anxiety-like behavior in mice. The effect was similar to that of corticotropin releasing factor (CRF) tested simultaneously for comparison. Recent studies have also demonstrated the presence of functional OX1 and OX2 receptors in human adipose tissue and their role in adipose tissue metabolism and adipogenesis (Digby et al., J. Endocrinol., 191, 129-36, 2006).

In summary, considering the wide variety of functions performed by the orexin system in awakening, sleep / wakefulness, appetite regulation, and the role they play in anxiety and stress responses, etc., drugs (or compounds) that target the orexin system are Sleep apnea, narcolepsy, insomnia, sleep-related complications, jet lag syndrome, circadian rhythm disorder, restless leg syndrome, sleep disorders, anxiety, depression, manic depression, obsessive-compulsive disorder, affective neuropathy, Depressive neuropathy, anxiety, mood disorders, delirium, panic attacks, post-traumatic stress disorder, sexual dysfunction, schizophrenia, psychosis, cognitive impairment, Alzheimer's and Parkinson's disease, dementia, mental retardation, dyskinesia E.g. Huntington's disease and Tourette syndrome, addiction, craving related to drug abuse, seizure disorders, epilepsy Psychiatric, neurological and neurodegenerative disorders, metabolic disorders such as obesity, diabetes, anorexia and anorexia and bulimia, asthma, migraine, pain, neuropathic pain, psychiatric, Sleep disorders associated with neurological and neurodegenerative disorders, neuropathic pain, increased or worsened sensitivity to pain, such as hyperalgesia, causalgia, and allodynia, acute pain, burn pain, back pain, complex local Diseases such as pain syndromes I and II, joint pain, post-stroke pain, postoperative pain, neuralgia, HIV infection-related pain, post-chemotherapy pain, irritable bowel syndrome and other diseases related to systemic dysfunction of the orexin system It is expected to have a beneficial therapeutic effect in the treatment of A number of documents, such as the following, explain what is currently known about the orexin pathway:
-Expert Opin. Ther. Patents (2006), 16 (5), 631-646
-Current Opinion in Drug Discovery & Development, 2006, 9 (5), 551-559
-J. Neurosci (2000), 20 (20), 7760-7765
-Neurosci Lett, (2003), 341 (3), 256-258

  The object of the present invention is to provide novel compounds of formula I, their preparation, medicaments based on the compounds according to the invention and their manufacture, and sleep apnea, narcolepsy, insomnia, sleep-related complications, jet lag syndrome, Rhythm disorder, restless leg syndrome, sleep disorder, anxiety, depression, manic depression, obsessive-compulsive disorder, affective neurosis, depressive neurosis, anxiety, mood disorder, delirium, panic attack disorder, mental Posttraumatic stress disorder, sexual dysfunction, schizophrenia, psychosis, cognitive impairment, Alzheimer's and Parkinson's disease, dementia, mental retardation, dyskinesia, such as Huntington's disease and Tourette syndrome, addiction, drug abuse related cravings, seizures Sexual disorders, epilepsy, psychiatric, neurological and neurodegenerative disorders, metabolic disorders such as obesity, diabetes, anorexia and bulimia Disorders, asthma, migraine, pain, neuropathic pain, sleep disorders associated with psychiatric, neurological and neurodegenerative disorders, neuropathic pain, increased or exacerbated sensitivity to pain, such as hyperalgesia, causalgia, And allodynia, acute pain, burn pain, back pain, combined regional pain syndromes I and II, joint pain, post-stroke pain, postoperative pain, neuralgia, HIV infection related pain, post-chemotherapy pain or irritable bowel Use of a compound of formula I for the control or prevention of diseases such as syndromes.

  The following definitions of general terms used herein apply regardless of whether the term in question appears alone or in combination.

  As used herein, the term “lower alkyl” refers to a straight or branched alkyl group having 1 to 7 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl. , T-butyl and the like. Preferred lower alkyl groups are groups having 1 to 4 carbon atoms.

The term “lower alkyl substituted by halogen” refers to an alkyl group as defined above, eg, —CF ₃ , —CHF ₂ , —CH ₂ F, —CH ₂ CF, wherein at least one hydrogen atom is replaced by halogen. _{3, -CF 2 CHF 2, -CH} 2 CH 2 CF 3, means such as -CH 2 _CF 2 _{CF 3.} Preferred lower alkyl substituted by a halogen group is a group having 1 to 4 carbon atoms.

  The term “lower alkoxy” is a group in which the alkyl residue is as defined above and is attached via an oxygen atom, eg methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, i-butoxy. , 2-butoxy, t-butoxy and the like. Preferred alkoxy groups are groups having 1 to 4 carbon atoms.

  The term “lower alkoxy substituted by halogen” means a group in which the alkyl residue is “lower alkyl substituted by halogen” as defined above, and bonded via an oxygen atom. To do. Preferred lower alkoxy substituted by a halogen group is a group having 1 to 4 carbon atoms.

  The term “halogen” means chlorine, iodine, fluorine and bromine.

  The term “aryl” means an aromatic monocyclic or bicyclic carbocyclic ring system such as phenyl or naphthyl, preferably phenyl.

  The term “heteroaryl” means a 5- or 6-membered aromatic ring system having 1 or 2 heteroatoms selected from O, S or N, such as isoxazolyl, oxazolyl, imidazolyl, pyridinyl and the like, preferably isoxazolyl To do.

  The term “pharmaceutically acceptable acid addition salt” refers to hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonic acid, p-toluenesulfone. Includes salts with inorganic acids and organic acids such as acids.

  Preferred compounds of formula I are those in which hetaryl is benzoxazol-2-yl

であり、例えば以下の例である：
｛３−［（６−クロロ−ベンゾオキサゾール−２−イルアミノ）−メチル］−ピロリジン−１−イル｝−（２，６−ジメトキシ−フェニル）−メタノン
｛（Ｓ）−３−［（６−クロロ−ベンゾオキサゾール−２−イルアミノ）−メチル］−ピロリジン−１−イル｝−（２，６−ジメトキシ−フェニル）−メタノン
｛（Ｓ）−３−［（６−クロロ−ベンゾオキサゾール−２−イルアミノ）−メチル］−ピロリジン−１−イル｝−（２−トリフルオロメチル−フェニル）−メタノン
｛（Ｓ）−３−［（６−クロロ−ベンゾオキサゾール−２−イルアミノ）−メチル］−ピロリジン−１−イル｝−（２−トリフルオロメトキシ−フェニル）−メタノン
｛（Ｓ）−３−［（６−クロロ−ベンゾオキサゾール−２−イルアミノ）−メチル］−ピロリジン−１−イル｝−［２−（１，１，２，２−テトラフルオロ−エトキシ）−フェニル］−メタノン
｛（Ｓ）−３−［（６−クロロ−ベンゾオキサゾール−２−イルアミノ）−メチル］−ピロリジン−１−イル｝−（５−メチル−２−トリフルオロメチル−フェニル）−メタノン
｛（Ｓ）−３−［（６−クロロ−ベンゾオキサゾール−２−イルアミノ）−メチル］−ピロリジン−１−イル｝−（５−メチル−３−フェニル−イソオキサゾール−４−イル）−メタノン
｛（Ｓ）−３−［（６−クロロ−ベンゾオキサゾール−２−イルアミノ）−メチル］−ピロリジン−１−イル｝−（５−フェニル−イソオキサゾール−４−イル）−メタノン
｛（Ｓ）−３−［（６−クロロ−ベンゾオキサゾール−２−イルアミノ）−メチル］−ピロリジン−１−イル｝−（２−クロロ−５−メチル−フェニル）−メタノン
｛（Ｓ）−３−［（６−クロロ−ベンゾオキサゾール−２−イルアミノ）−メチル］−ピロリジン−１−イル｝−（２−メトキシ−５−メチル−フェニル）−メタノン
｛（Ｓ）−３−［（７−フルオロ−ベンゾオキサゾール−２−イルアミノ）−メチル］−ピロリジン−１−イル｝−（２−トリフルオロメトキシ−フェニル）−メタノン
｛（Ｓ）−３−［（７−フルオロ−ベンゾオキサゾール−２−イルアミノ）−メチル］−ピロリジン−１−イル｝−［２−（１，１，２，２−テトラフルオロ−エトキシ）−フェニル］−メタノン
｛（Ｓ）−３−［（７−フルオロ−ベンゾオキサゾール−２−イルアミノ）−メチル］−ピロリジン−１−イル｝−（５−メチル−２−トリフルオロメチル−フェニル）−メタノン
｛（Ｓ）−３−［（７−フルオロ−ベンゾオキサゾール−２−イルアミノ）−メチル］−ピロリジン−１−イル｝−（５−メチル−３−フェニル−イソオキサゾール−４−イル）−メタノン
｛（Ｓ）−３−［（７−フルオロ−ベンゾオキサゾール−２−イルアミノ）−メチル］−ピロリジン−１−イル｝−（５−フェニル−イソオキサゾール−４−イル）−メタノン
（２−クロロ−５−メチル−フェニル）−｛（Ｓ）−３−［（７−フルオロ−ベンゾオキサゾール−２−イルアミノ）−メチル］−ピロリジン−１−イル｝−メタノン又は
｛（Ｓ）−３−［（７−フルオロ−ベンゾオキサゾール−２−イルアミノ）−メチル］−ピロリジン−１−イル｝−（２−メトキシ−５−メチル−フェニル）−メタノン。

For example, the following example:
{3-[(6-Chloro-benzoxazol-2-ylamino) -methyl] -pyrrolidin-1-yl}-(2,6-dimethoxy-phenyl) -methanone {(S) -3-[(6-chloro -Benzoxazol-2-ylamino) -methyl] -pyrrolidin-1-yl}-(2,6-dimethoxy-phenyl) -methanone {(S) -3-[(6-chloro-benzoxazol-2-ylamino) -Methyl] -pyrrolidin-1-yl}-(2-trifluoromethyl-phenyl) -methanone {(S) -3-[(6-chloro-benzoxazol-2-ylamino) -methyl] -pyrrolidine-1- Yl}-(2-trifluoromethoxy-phenyl) -methanone {(S) -3-[(6-chloro-benzoxazol-2-ylamino) -methyl] -pyrrolidi N-1-yl}-[2- (1,1,2,2-tetrafluoro-ethoxy) -phenyl] -methanone {(S) -3-[(6-chloro-benzoxazol-2-ylamino)- Methyl] -pyrrolidin-1-yl}-(5-methyl-2-trifluoromethyl-phenyl) -methanone {(S) -3-[(6-chloro-benzoxazol-2-ylamino) -methyl] -pyrrolidine -1-yl}-(5-methyl-3-phenyl-isoxazol-4-yl) -methanone {(S) -3-[(6-chloro-benzoxazol-2-ylamino) -methyl] -pyrrolidine- 1-yl}-(5-phenyl-isoxazol-4-yl) -methanone {(S) -3-[(6-chloro-benzoxazol-2-ylamino) -methyl] -pyrrolidine-1 -Yl}-(2-chloro-5-methyl-phenyl) -methanone {(S) -3-[(6-chloro-benzoxazol-2-ylamino) -methyl] -pyrrolidin-1-yl}-(2 -Methoxy-5-methyl-phenyl) -methanone {(S) -3-[(7-fluoro-benzoxazol-2-ylamino) -methyl] -pyrrolidin-1-yl}-(2-trifluoromethoxy-phenyl ) -Methanone {(S) -3-[(7-fluoro-benzoxazol-2-ylamino) -methyl] -pyrrolidin-1-yl}-[2- (1,1,2,2-tetrafluoro-ethoxy) ) -Phenyl] -methanone {(S) -3-[(7-fluoro-benzoxazol-2-ylamino) -methyl] -pyrrolidin-1-yl}-(5-methyl-2-triflu) Oromethyl-phenyl) -methanone {(S) -3-[(7-fluoro-benzoxazol-2-ylamino) -methyl] -pyrrolidin-1-yl}-(5-methyl-3-phenyl-isoxazole-4 -Yl) -methanone {(S) -3-[(7-fluoro-benzoxazol-2-ylamino) -methyl] -pyrrolidin-1-yl}-(5-phenyl-isoxazol-4-yl) -methanone (2-chloro-5-methyl-phenyl)-{(S) -3-[(7-fluoro-benzoxazol-2-ylamino) -methyl] -pyrrolidin-1-yl} -methanone or {(S)- 3-[(7-Fluoro-benzoxazol-2-ylamino) -methyl] -pyrrolidin-1-yl}-(2-methoxy-5-methyl-phenyl) -methano N.

Preferred compounds of formula I-1 as defined above are
{3-[(6-Chloro-benzoxazol-2-ylamino) -methyl] -pyrrolidin-1-yl}-(2,6-dimethoxy-phenyl) -methanone {(S) -3-[(6-chloro -Benzoxazol-2-ylamino) -methyl] -pyrrolidin-1-yl}-(2,6-dimethoxy-phenyl) -methanone {(S) -3-[(6-chloro-benzoxazol-2-ylamino) -Methyl] -pyrrolidin-1-yl}-(5-methyl-3-phenyl-isoxazol-4-yl) -methanone or {(S) -3-[(7-fluoro-benzoxazol-2-ylamino) -Methyl] -pyrrolidin-1-yl}-(5-methyl-3-phenyl-isoxazol-4-yl) -methanone.

  Preferred compounds of formula I are further compounds wherein hetaryl is benzothiazol-2-yl

であり、例えば以下の例である：
｛（Ｓ）−３−［（６−フルオロ−ベンゾチアゾール−２−イルアミノ）−メチル］−ピロリジン−１−イル｝−（２−トリフルオロメチル−フェニル）−メタノン
｛（Ｓ）−３−［（６−フルオロ−ベンゾチアゾール−２−イルアミノ）−メチル］−ピロリジン−１−イル｝−（２−トリフルオロメトキシ−フェニル）−メタノン
｛（Ｓ）−３−［（６−フルオロ−ベンゾチアゾール−２−イルアミノ）−メチル］−ピロリジン−１−イル｝−［２−（１，１，２，２−テトラフルオロ−エトキシ）−フェニル］−メタノン
｛（Ｓ）−３−［（６−フルオロ−ベンゾチアゾール−２−イルアミノ）−メチル］−ピロリジン−１−イル｝−（５−メチル−２−トリフルオロメチル−フェニル）−メタノン
｛（Ｓ）−３−［（６−フルオロ−ベンゾチアゾール−２−イルアミノ）−メチル］−ピロリジン−１−イル｝−（５−メチル−３−フェニル−イソオキサゾール−４−イル）−メタノン
｛（Ｓ）−３−［（６−フルオロ−ベンゾチアゾール−２−イルアミノ）−メチル］−ピロリジン−１−イル｝−（５−フェニル−イソオキサゾール−４−イル）−メタノン
（２−クロロ−５−メチル−フェニル）−｛（Ｓ）−３−［（６−フルオロ−ベンゾチアゾール−２−イルアミノ）−メチル］−ピロリジン−１−イル｝−メタノン又は
｛（Ｓ）−３−［（６−フルオロ−ベンゾチアゾール−２−イルアミノ）−メチル］−ピロリジン−１−イル｝−（２−メトキシ−５−メチル−フェニル）−メタノン。

For example, the following example:
{(S) -3-[(6-Fluoro-benzothiazol-2-ylamino) -methyl] -pyrrolidin-1-yl}-(2-trifluoromethyl-phenyl) -methanone {(S) -3- [ (6-Fluoro-benzothiazol-2-ylamino) -methyl] -pyrrolidin-1-yl}-(2-trifluoromethoxy-phenyl) -methanone {(S) -3-[(6-Fluoro-benzothiazole- 2-ylamino) -methyl] -pyrrolidin-1-yl}-[2- (1,1,2,2-tetrafluoro-ethoxy) -phenyl] -methanone {(S) -3-[(6-fluoro- Benzothiazol-2-ylamino) -methyl] -pyrrolidin-1-yl}-(5-methyl-2-trifluoromethyl-phenyl) -methanone {(S) -3-[(6-fluoro- Benzothiazol-2-ylamino) -methyl] -pyrrolidin-1-yl}-(5-methyl-3-phenyl-isoxazol-4-yl) -methanone {(S) -3-[(6-fluoro-benzo Thiazol-2-ylamino) -methyl] -pyrrolidin-1-yl}-(5-phenyl-isoxazol-4-yl) -methanone (2-chloro-5-methyl-phenyl)-{(S) -3- [(6-Fluoro-benzothiazol-2-ylamino) -methyl] -pyrrolidin-1-yl} -methanone or {(S) -3-[(6-Fluoro-benzothiazol-2-ylamino) -methyl]- Pyrrolidin-1-yl}-(2-methoxy-5-methyl-phenyl) -methanone.

Preferred compounds of formula I-2 as defined above are
{(S) -3-[(6-Fluoro-benzothiazol-2-ylamino) -methyl] -pyrrolidin-1-yl}-[2- (1,1,2,2-tetrafluoro-ethoxy) -phenyl ] -Methanone {(S) -3-[(6-Fluoro-benzothiazol-2-ylamino) -methyl] -pyrrolidin-1-yl}-(5-methyl-3-phenyl-isoxazol-4-yl) -Methanone or {(S) -3-[(6-fluoro-benzothiazol-2-ylamino) -methyl] -pyrrolidin-1-yl}-(5-phenyl-isoxazol-4-yl) -methanone .

Preferred compounds of formula I are further compounds wherein hetaryl is quinoxalin-2-yl

であり、例えば以下の例である：
｛（Ｓ）−３−［（６−クロロ−キノキサリン−２−イルアミノ）−メチル］−ピロリジン−１−イル｝−（２−トリフルオロメトキシ−フェニル）−メタノン
｛（Ｓ）−３−［（６−クロロ−キノキサリン−２−イルアミノ）−メチル］−ピロリジン−１−イル｝−［２−（１，１，２，２−テトラフルオロ−エトキシ）−フェニル］−メタノン
｛（Ｓ）−３−［（６−クロロ−キノキサリン−２−イルアミノ）−メチル］−ピロリジン−１−イル｝−（５−メチル−２−トリフルオロメチル−フェニル）−メタノン
｛（Ｓ）−３−［（６−クロロ−キノキサリン−２−イルアミノ）−メチル］−ピロリジン−１−イル｝−（５−メチル−３−フェニル−イソオキサゾール−４−イル）−メタノン
｛（Ｓ）−３−［（６−クロロ−キノキサリン−２−イルアミノ）−メチル］−ピロリジン−１−イル｝−（５−フェニル−イソオキサゾール−４−イル）−メタノン
（２−クロロ−５−メチル−フェニル）−｛（Ｓ）−３−［（６−クロロ−キノキサリン−２−イルアミノ）−メチル］−ピロリジン−１−イル｝−メタノン又は
｛（Ｓ）−３−［（６−クロロ−キノキサリン−２−イルアミノ）−メチル］−ピロリジン−１−イル｝−（２−メトキシ−５−メチル−フェニル）−メタノン。

For example, the following example:
{(S) -3-[(6-Chloro-quinoxalin-2-ylamino) -methyl] -pyrrolidin-1-yl}-(2-trifluoromethoxy-phenyl) -methanone {(S) -3-[( 6-chloro-quinoxalin-2-ylamino) -methyl] -pyrrolidin-1-yl}-[2- (1,1,2,2-tetrafluoro-ethoxy) -phenyl] -methanone {(S) -3- [(6-Chloro-quinoxalin-2-ylamino) -methyl] -pyrrolidin-1-yl}-(5-methyl-2-trifluoromethyl-phenyl) -methanone {(S) -3-[(6-chloro -Quinoxalin-2-ylamino) -methyl] -pyrrolidin-1-yl}-(5-methyl-3-phenyl-isoxazol-4-yl) -methanone {(S) -3-[(6-chloro-quinoki Salin-2-ylamino) -methyl] -pyrrolidin-1-yl}-(5-phenyl-isoxazol-4-yl) -methanone (2-chloro-5-methyl-phenyl)-{(S) -3- [(6-Chloro-quinoxalin-2-ylamino) -methyl] -pyrrolidin-1-yl} -methanone or {(S) -3-[(6-Chloro-quinoxalin-2-ylamino) -methyl] -pyrrolidine- 1-yl}-(2-methoxy-5-methyl-phenyl) -methanone.

Preferred compounds of formula I-3 as defined above are
{(S) -3-[(6-Chloro-quinoxalin-2-ylamino) -methyl] -pyrrolidin-1-yl}-[2- (1,1,2,2-tetrafluoro-ethoxy) -phenyl] -Methanone.

Preferred compounds as defined above are those in which R ¹ is Cl or F. Another preferred compound as defined above is a compound wherein n is 1.

Other preferred compounds as defined above are compounds wherein R ² is lower alkyl, lower alkoxy, lower alkoxy substituted by halogen, or phenyl, especially R ² is methyl, methoxy, 1,1,2,2-tetra A compound that is fluoro-ethoxy or phenyl.

  Preferably, m is 1 or 2. Another preferred compound as defined above is a compound wherein Ar is phenyl or isoxazolyl.

The compounds of the present invention represented by formula I and pharmaceutically acceptable salts thereof can be prepared by methods known in the art according to the following steps:
a) Formula

で示される化合物を、式

A compound represented by the formula

で示される化合物又はそれに対応する酸クロリドと反応させて、式

Is reacted with a compound represented by the formula:

で示される化合物にすること
［ここで、Ｒ^１、Ｒ^２、Ａｒ、ヘタリール、ｍ及びｎは、前記と同義である］、
及び必要があれば、得られた化合物を薬学的に許容される酸付加塩に変換すること
を含む。

[Wherein R ¹ , R ² , Ar, hetaryl, m and n are as defined above],
And if necessary, converting the resulting compound to a pharmaceutically acceptable acid addition salt.

General experimental section:
The preparation of the compounds of formula I according to the invention can be carried out by continuous or convergent synthetic routes. The synthesis of the compounds of the present invention is shown in the following scheme. The skills required for carrying out the reaction and purification of the resulting products are known to those skilled in the art. Substituents and indicators used in the description of the following steps have the meanings indicated above in this specification unless the opposite meaning is indicated.

  In more detail, the compounds of formula I can be manufactured by the methods given below, by the methods given in the examples or by methods analogous thereto. Suitable reaction conditions for the individual reaction steps are known to the person skilled in the art. The reaction sequence is not limited to the sequence shown in Scheme 1, and the order of the reaction steps can be freely changed depending on the starting materials and their respective reactivities. Starting materials are commercially available or are prepared by methods analogous to those shown below, by methods described in references or examples cited in the specification, or by methods known in the art Can be either.

Stage a)
Aromatic heterocyclic compounds II are either commercially available or are available in the literature (for the reaction conditions described in the literature affecting such reactions, see eg: Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition Can be synthesized, for example, from their respective hetaryl (HET) -OH derivatives, according to the procedure described in C. Larock. John Wiley & Sons, New York, NY 1999). One of them. The protected amino-methylpyrrolidine III is commercially available or can be synthesized according to procedures described in the literature. The protected amino-methylpyrrolidine III can be reacted with II in the presence or absence of a solvent and in the presence or absence of a base. There is no particular restriction on the nature of the solvent to be employed, provided that the solvent does not have a detrimental effect on the reaction or reagent involved and that the solvent can dissolve the reagent at least to some extent. Examples of suitable solvents include dichloromethane (DCM), dimethylformamide (DMF), tetrahydrofuran (THF) and the like. There is no particular restriction on the nature of the base used at this stage, and any base commonly used in this type of reaction can equally be employed here. Examples of such bases include NEt ₃ , DIPEA and the like. The exact reaction temperature is not critical to the invention since the reaction can be carried out over a wide range of temperatures. It is convenient to carry out the reaction by heating from ambient temperature to reflux. The time required for the reaction can also vary widely depending on a number of factors, particularly the reaction temperature and the nature of the reagents. However, a period of 0.5 hours to several days will usually be sufficient to recover the protected intermediate (convenient PG = Boc). The intermediate can be subjected to acidic cleavage of the protecting group in the presence of a solvent. There is no particular restriction on the nature of the solvent to be employed, provided that the solvent does not have a detrimental effect on the reaction or reagent involved and that the solvent can be at least partially dissolved in the reagent. Examples of suitable solvents include dichloromethane (DCM), dioxane, tetrahydrofuran (THF) and the like. There is no limitation on the nature of the acid used in this stage, and any acid commonly used in this type of reaction can equally be employed here. Examples of such acids include HCl and the like. The reaction can be carried out over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. It is convenient to carry out the reaction by heating from ambient temperature to reflux. The time required for the reaction can also vary widely depending on a number of factors, particularly the reaction temperature and the nature of the reagents. However, a period of 0.5 hours to several days will usually be sufficient to recover the aminomethyl-pyrrolidine derivative IV.

Step b)
Conversion of the intermediate aminomethyl-pyrrolidine derivative IV with acid (in coupling conditions with a coupling agent) or acid chloride V is well known in the art. For similar examples in the literature, see Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition, Richard C. Larock. John Wiley & Sons, New York, NY. However, the inventors have found it convenient to react the intermediate aminomethyl-pyrrolidine derivative IV with an acid chloride in the presence or absence of a base and in the presence or absence of a solvent. There is no particular restriction on the nature of the solvent to be employed, provided that the solvent has no detrimental effect on the reaction or reagent involved and that the solvent can dissolve the reagent at least to some extent. Examples of suitable solvents include dichloromethane (DCM), dimethylformamide (DMF), tetrahydrofuran (THF) and the like. There is no particular restriction on the nature of the base used in this stage, and any base commonly used in this type of reaction can equally be employed here. Examples of such bases include pyridine, NEt ₃ , DIPEA and the like. The reaction can be carried out over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. It is convenient to carry out the reaction by heating from ambient temperature to reflux. The time required for the reaction can also vary widely depending on a number of factors, particularly the reaction temperature and the nature of the reagents. However, a period of 0.5 hours to several days will usually be sufficient to recover the aminomethyl-pyrrolidine derivative I.

  These compounds were examined by the tests described later in this specification.

Intracellular Ca ²⁺ Mobilization Assay A Chinese hamster ovary (dHFr-) mutant cell line stably expressing human orexin-1 (hOX1) or human orexin-2 (hOX2) receptor is obtained at 4500 mg / L GlutaMax ™ ) -1, D-glucose and sodium pyruvate (Catalog No. 31966-021, Invitrogen, Carlsbad, CA), 5% dialyzed fetal calf serum (Catalog No. 26400-044), 100 μg / ml penicillin and 100 μg / ml streptomycin Maintained in Dulbecco's Modified Eagle Medium (1 ×). 5 × 10 ⁴ cells / well were seeded in poly-D-lysine treated 96-well black / clear bottom plates (Cat. # BD356640, BD Biosciences, Palo Alto, Calif.). 24 hours later, 4 μM Flou-4 acetoxymethyl ester (Catalog No. F-14202, Molecular Probes, Eugene, OR) in FLIPR buffer (1 × HBSS, 20 mM HEPES, 2.5 mM probenecid) for 1 hour at 37 ° C. Loaded. Hanks Balanced Salt Solution (HBSS) (10 ×) (Catalog Number 14065-049) and HEPES (1M) (Catalog Number 15630-056) were purchased from Invitrogen (Carlsbad, Calif.). Probenecid (250 mM) (Cat. No. P8761) was purchased from Sigma (Buchs, Switzerland). Cells were washed 5 times with FLIPR buffer to remove excess dye, and intracellular calcium mobilization [Ca ²⁺ ] _i was analyzed using a fluorescence imaging plate reader (FLIPR-96, Molecular Devices, Menlo Park, as previously described). , CA) (Malherbe et al., Mol. Pharmacol., 64, 823-832, 2003). Orexin A (catalog number 1455, Toris Cookson Ltd, Bristol, UK) was used as an agonist. Orexin A (50 mM stock solution in DMSO) was diluted in FLIPR buffer + 0.1% BSA. Orexin-A EC ₅₀ and EC ₈₀ values were measured daily from standard curves of agonist concentration-response in CHO (dHFr-)-OX1R and -OX2R cell lines. All compounds were dissolved in 100% DMSO. Inhibition curves with the addition of 11 concentrations of inhibitory compounds (0.0001-10 μM) and with the EC ₈₀ value of orexin-A as an agonist (concentration determined daily, giving 80% of the maximum agonist response). It was determined. Antagonists were applied 25 minutes before applying the agonist (incubation at 37 ° C.). The response was measured as the fluorescence increase peak minus the basal value and normalized to the maximum stimulatory effect induced by the orexin-A or orexin-B EC ₈₀ value. The inhibition curve was fitted to Hill's equation: y = 100 / (1+ (x / IC ₅₀ ) ^nH ), where n _H = slope coefficient using Excel-fit 4 software (Microsoft). The K _b value was calculated according to the following formula: K _b = IC ₅₀ / (1+ [A] / EC ₅₀ ) [where A is the concentration of agonist added and is very close to the EC ₈₀ value of the agonist. Nearly, IC ₅₀ and EC ₅₀ values were obtained from antagonist inhibition curves and orexin-A or B agonist curves, respectively.

These compounds exhibit _Kb values as shown in the table below for the orexin receptor in humans.

  The compounds of formula I and the pharmaceutically acceptable salts of the compounds of formula I can be used as medicaments, eg in the form of pharmaceutical preparations. The pharmaceutical preparation can be administered orally, for example, in the form of tablets, coatings, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions. However, administration can also take place rectally, for example in the form of suppositories, or parenterally, for example in the form of injections.

  The compounds of formula I can be formulated with pharmaceutically inert, inorganic or organic carriers to produce pharmaceutical preparations. Lactose, corn starch or derivatives thereof, talc, stearic acid or their salts and the like can be used as such carriers, for example for tablets, coatings, dragees and hard gelatine capsules. Suitable carriers for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semisolid and liquid polyols and the like. However, depending on the nature of the active substance, a soft gelatin capsule usually does not require a carrier. Suitable carriers for the production of solutions and syrups are, for example, water, polyols, glycerin, vegetable oils and the like. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.

  In addition, the pharmaceutical formulation contains preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavoring agents, salts that change osmotic pressure, buffers, masking agents or antioxidants. be able to. They can also contain other therapeutically valuable substances.

  A medicament containing a compound of formula I, or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier is also desirable with one or more of the compound of formula I and / or a pharmaceutically acceptable acid addition salt. Thus, it is an object of the present invention, as well as a preparation method comprising preparing one or more other therapeutically valuable substances together with one or more of a therapeutically inert carrier.

  Another object of the present invention is sleep apnea, narcolepsy, insomnia, parasomnia, jet lag syndrome, circadian rhythm disorder, sleep disorders including restless leg syndrome, anxiety, depression, manic depression Obsessive compulsive disorder, affective neuropathy, depressive neurosis, anxiety, mood disorder, delirium, panic attack disorder, post-traumatic stress disorder, sexual dysfunction, schizophrenia, psychosis, cognitive impairment, Alzheimer's disease and Parkinson Diseases, dementia, mental retardation, dyskinesia such as Huntington's disease and Tourette's syndrome, addiction, craving related to drug abuse, seizure disorders, psychiatric, neurological and neurodegenerative disorders including epilepsy, obesity, diabetes, etc. Related to metabolic disorders, eating disorders including anorexia and bulimia, asthma, migraine, pain, neuropathic pain, psychiatric, neurological and neurodegenerative disorders Increased or excessive sensitivity to pain, such as sleep disorders, neuropathic pain, hyperalgesia, causalgia, and allodynia, acute pain, burn pain, back pain, combined local pain syndromes I and II, joint pain, A method for therapeutic and / or prophylactic treatment of post-stroke pain, postoperative pain, neuralgia, pain associated with HIV infection, post-chemotherapy pain, or irritable bowel syndrome, the method being human or animal Administration of a compound as defined above.

  The most preferred indications according to the present invention are sleep apnea, narcolepsy, insomnia, parasomnia, jet lag syndrome, circadian rhythm disorders, sleep disorders including restless leg syndrome, anxiety, depression, manic depression Obsessive compulsive disorder, affective neuropathy, depressive neurosis, anxiety, mood disorder, delirium, panic attack disorder, post-traumatic stress disorder, sexual dysfunction, schizophrenia, psychosis, cognitive impairment, Alzheimer's disease and Parkinson Diseases, dementia, mental retardation, dyskinesia such as Huntington's disease and Tourette's syndrome, addiction, craving related to drug abuse, seizure disorders, psychiatric, neurological and neurodegenerative disorders including epilepsy, obesity, diabetes, etc. For metabolic disorders, anorexia including anorexia and bulimia, asthma, migraine, pain, neuropathic pain, psychiatric, neurological and neurodegenerative disorders Increased or excessive susceptibility to pain, such as continuous sleep disorders, neuropathic pain, hyperalgesia, causalgia, and allodynia, acute pain, burn pain, back pain, complex regional pain syndromes I and II, joints It includes pain, post-stroke pain, postoperative pain, neuralgia, pain associated with HIV infection, post-chemotherapy pain, irritable bowel syndrome and other diseases associated with systemic orexin dysfunction. The most preferred indications are sleep disorders, particularly sleep disorders associated with apnea, narcolepsy, insomnia, abnormal sleep behavior, jet lag syndrome and neurological disorders.

  The dose can vary within wide limits and must of course be adapted to the individual requirements in each particular case. For oral administration, adult dosages can vary from about 0.01 mg to about 1000 mg per day of the compound of general formula I, or corresponding amounts of pharmaceutically acceptable salts thereof. The daily dose may be administered as a single dose or in divided doses, and in addition, the upper limit may be exceeded if the need is indicated.

Tablet formulation (wet granulation)
Item Ingredients mg / tablet
5mg 25mg 100mg 500mg
1. Compound of formula I 5 25 100 500
2. Anhydrous lactose DTG 125 105 30 150
3. Sta-Rx 1500 6 6 6 30
4). Microcrystalline cellulose 30 30 30 150
5. Magnesium stearate 1 1 1 1
Total 167 167 167 831

Manufacturing procedure Mix items 1, 2, 3 and 4 and granulate with purified water.
2. The granules are dried at 50 ° C.
3. Pass the granules through a suitable milling machine.
4). Add item 5 and mix for 3 minutes; compress on a suitable machine.

Capsule prescription item Ingredients mg / capsule
5mg 25mg 100mg 500mg
1. Compound of formula I 5 25 100 500
2. Hydrous lactose 159 123 148 ---
3. Corn starch 25 35 40 70
4). Talc 10 15 10 25
5. Magnesium stearate 1 2 2 5
Total 200 200 300 600

Manufacturing procedure Mix items 1, 2 and 3 in a suitable mixer for 30 minutes.
2. Add items 4 and 5 and mix for 3 minutes.
3. Fill into suitable capsules.

Experimental part:

Example 1
{3-[(6-Chloro-benzoxazol-2-ylamino) -methyl] -pyrrolidin-1-yl}-(2,6-dimethoxy-phenyl) -methanone

a) Step 1:
3-[(6-Chloro-benzoxazol-2-ylamino) -methyl] -pyrrolidine-1-carboxylic acid tert-butyl ester

3-Aminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (commercial) 220 mg (1.1 mmol), 2,6-dichloro-benzoxazole (commercial) 188 mg (1 mmol) and NEt ₃ 303 mg ( ₃ mmol) in 4 mL of DCM ) Was stirred overnight at room temperature. After evaporation to dryness, the residue was purified by flash column chromatography on silica eluting with a gradient formed from ethyl acetate and heptane. The product containing fractions were evaporated to give 351 mg (99%) of the title compound. MS (m / e): 352.4 (MH ^< ^{+ >} ).

b) Step 2:
(6-Chloro-benzoxazol-2-yl) -pyrrolidin-3-ylmethyl-amine hydrochloride

A mixture of 350.2 mg (0.99 mmol) of 3-[(6-chloro-benzoxazol-2-ylamino) -methyl] -pyrrolidine-1-carboxylic acid tert-butyl ester and 3 mL of 4N HCl in dioxane is stirred at room temperature. Stir overnight. The mixture was decanted and the residue was evaporated to dryness to give the title compound, which was used in the subsequent step without further purification. MS (m / e): 252.2 (MH ^< ^{+ >} ).

c) Step 3:
{3-[(6-Chloro-benzoxazol-2-ylamino) -methyl] -pyrrolidin-1-yl}-(2,6-dimethoxy-phenyl) -methanone (6-Chloro-benzoxazole- in 2 mL of DCM 2-yl) -pyrrolidin-3-ylmethyl-amine; a mixture of 20 mg (0.07 mmol) hydrochloride, 15 mg (0.77 mmol) 2,6-dimethoxybenzoyl chloride and 10 mg (0.1 mmol) NEt ₃ at room temperature. Shake overnight. After evaporation, the residue was subjected to purification by preparative HPLC on reverse phase eluting with a gradient formed from acetonitrile, water and formic acid. The product containing fractions were evaporated to give 6.5 mg (22%) of the title compound. MS (m / e): 416.2 (MH ^< ^{+ >} ).

Intermediate 1
(6-Chloro-benzoxazol-2-yl)-(R) -1-pyrrolidin-3-ylmethyl-amine hydrochloride

In a manner similar to that described in the synthesis of (6-Chloro-benzoxazol-2-yl) -pyrrolidin-3-ylmethyl-amine; hydrochloride (Example 1, Step 2), the title compound is Prepared from 3-aminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester and 2,6-dichloro-benzoxazole (commercially available) followed by treatment with HCl in dioxane Cleavage of the protecting group was performed. MS (m / e): 252.2 (MH ^< ^{+ >} ).

Intermediate 2
(6-Fluoro-benzothiazol-2-yl)-(R) -1-pyrrolidin-3-ylmethyl-amine hydrochloride

In a manner similar to that described in the synthesis of (6-Chloro-benzoxazol-2-yl) -pyrrolidin-3-ylmethyl-amine; hydrochloride (Example 1, Step 2), the title compound is Prepared from 3-aminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester and 2-chloro-6-fluoro-benzothiazole (commercially available) followed by treatment with HCl in dioxane Cleavage of the carbonyl-protecting group was performed. MS (m / e): 252.1 (MH ^< ^{+ >} ).

Intermediate 3
(7-Fluoro-benzoxazol-2-yl)-(R) -1-pyrrolidin-3-ylmethyl-amine hydrochloride

In a manner similar to that described in the synthesis of (6-Chloro-benzoxazol-2-yl) -pyrrolidin-3-ylmethyl-amine; hydrochloride (Example 1, Step 2), the title compound is Prepared from -3-aminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester and 2-chloro-7-fluoro-benzoxazole (Bioorganic & Medicinal Chemistry Letters 2007, 17, 4689), followed by in dioxane Cleavage of the tert-butyloxycarbonyl-protecting group was carried out by treatment with HCl. MS (m / e): 236.1 (MH ^< ^{+ >} ).

Intermediate 4
(6-Chloro-quinoxalin-2-yl)-(R) -1-pyrrolidin-3-ylmethyl-amine

In a manner similar to that described in the synthesis of (6-Chloro-benzoxazol-2-yl) -pyrrolidin-3-ylmethyl-amine; hydrochloride (Example 1, Step 2), the title compound is Prepared from -3-aminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester and 2,6-dichloro-quinoxaline (commercially available) followed by tert-butyloxycarbonyl-protection by treatment with HCl in dioxane Group cleavage was performed. MS (m / e): 263.1 (MH ^< ^{+ >} ).

Example 2
{(S) -3-[(6-Chloro-benzoxazol-2-ylamino) -methyl] -pyrrolidin-1-yl}-(2,6-dimethoxy-phenyl) -methanone

146.3 mg (0.45 mmol) (6-chloro-benzoxazol-2-yl)-(R) -1-pyrrolidin-3-ylmethyl-amine hydrochloride (intermediate 1) in 4 mL DMF and 0.3 mL DIPEA , 2,6-dimethoxy-benzoic acid (commercially available) 106.7 mg (0.586 mmol) and TBTU 206.9 mg (0.64 mmol) were shaken overnight at room temperature. The mixture was acidified with formic acid and subjected to purification by preparative HPLC on reverse phase eluting with a gradient formed from acetonitrile, water and formic acid. The product containing fractions were evaporated to give 72 mg (38%) of the title compound. MS (m / e): 416.2 (MH ^< ^{+ >} ).

  For the synthesis of {(S) -3-[(6-chloro-benzooxazol-2-ylamino) -methyl] -pyrrolidin-1-yl}-(2,6-dimethoxy-phenyl) -methanone (Example 2) In analogy to the described procedure, further pyrrolidin-3-ylmethyl-amine derivatives have been synthesized from each of these starting materials as mentioned in Table 1. Table 1 includes Examples 3 to 32.

Claims (23)

formula

[Where:
R ¹ is halogen;
R ² is halogen, lower alkyl, lower alkoxy, lower alkyl substituted with halogen, lower alkoxy substituted with halogen, or phenyl;
Hetariru

(X is O or S);
Ar is aryl or heteroaryl;
n is 0, 1 or 2;
m is 0, 1 or 2; or a pharmaceutically suitable acid addition salt, optically pure enantiomer, racemate or diastereomeric mixture thereof. The formula I-1 of claim 1

[Wherein R ¹ is halogen;
R ² is halogen, lower alkyl, lower alkoxy, lower alkyl substituted with halogen, lower alkoxy substituted with halogen, or phenyl;
Ar is aryl or heteroaryl;
n is 0, 1 or 2;
m is 0, 1 or 2]
Or a pharmaceutically suitable acid addition salt, optically pure enantiomer, racemate or diastereomeric mixture thereof. {3-[(6-Chloro-benzoxazol-2-ylamino) -methyl] -pyrrolidin-1-yl}-(2,6-dimethoxy-phenyl) -methanone {(S) -3-[(6-chloro -Benzoxazol-2-ylamino) -methyl] -pyrrolidin-1-yl}-(2,6-dimethoxy-phenyl) -methanone {(S) -3-[(6-chloro-benzoxazol-2-ylamino) -Methyl] -pyrrolidin-1-yl}-(2-trifluoromethyl-phenyl) -methanone {(S) -3-[(6-chloro-benzoxazol-2-ylamino) -methyl] -pyrrolidine-1- Yl}-(2-trifluoromethoxy-phenyl) -methanone {(S) -3-[(6-chloro-benzoxazol-2-ylamino) -methyl] -pyrrolidi N-1-yl}-[2- (1,1,2,2-tetrafluoro-ethoxy) -phenyl] -methanone {(S) -3-[(6-chloro-benzoxazol-2-ylamino)- Methyl] -pyrrolidin-1-yl}-(5-methyl-2-trifluoromethyl-phenyl) -methanone {(S) -3-[(6-chloro-benzoxazol-2-ylamino) -methyl] -pyrrolidine -1-yl}-(5-methyl-3-phenyl-isoxazol-4-yl) -methanone {(S) -3-[(6-chloro-benzoxazol-2-ylamino) -methyl] -pyrrolidine- 1-yl}-(5-phenyl-isoxazol-4-yl) -methanone {(S) -3-[(6-chloro-benzoxazol-2-ylamino) -methyl] -pyrrolidine-1 -Yl}-(2-chloro-5-methyl-phenyl) -methanone {(S) -3-[(6-chloro-benzoxazol-2-ylamino) -methyl] -pyrrolidin-1-yl}-(2 -Methoxy-5-methyl-phenyl) -methanone {(S) -3-[(7-fluoro-benzoxazol-2-ylamino) -methyl] -pyrrolidin-1-yl}-(2-trifluoromethoxy-phenyl ) -Methanone {(S) -3-[(7-fluoro-benzoxazol-2-ylamino) -methyl] -pyrrolidin-1-yl}-[2- (1,1,2,2-tetrafluoro-ethoxy) ) -Phenyl] -methanone {(S) -3-[(7-fluoro-benzoxazol-2-ylamino) -methyl] -pyrrolidin-1-yl}-(5-methyl-2-triflu) Oromethyl-phenyl) -methanone {(S) -3-[(7-fluoro-benzoxazol-2-ylamino) -methyl] -pyrrolidin-1-yl}-(5-methyl-3-phenyl-isoxazole-4 -Yl) -methanone {(S) -3-[(7-fluoro-benzoxazol-2-ylamino) -methyl] -pyrrolidin-1-yl}-(5-phenyl-isoxazol-4-yl) -methanone (2-chloro-5-methyl-phenyl)-{(S) -3-[(7-fluoro-benzoxazol-2-ylamino) -methyl] -pyrrolidin-1-yl} -methanone or {(S)- 3-[(7-Fluoro-benzoxazol-2-ylamino) -methyl] -pyrrolidin-1-yl}-(2-methoxy-5-methyl-phenyl) -methano The compound of formula I-1 according to claim 2, which is {3-[(6-Chloro-benzoxazol-2-ylamino) -methyl] -pyrrolidin-1-yl}-(2,6-dimethoxy-phenyl) -methanone {(S) -3-[(6-chloro -Benzoxazol-2-ylamino) -methyl] -pyrrolidin-1-yl}-(2,6-dimethoxy-phenyl) -methanone {(S) -3-[(6-chloro-benzoxazol-2-ylamino) -Methyl] -pyrrolidin-1-yl}-(5-methyl-3-phenyl-isoxazol-4-yl) -methanone or {(S) -3-[(7-fluoro-benzoxazol-2-ylamino) The compound of formula I-1 according to claim 2, which is -methyl] -pyrrolidin-1-yl}-(5-methyl-3-phenyl-isoxazol-4-yl) -methanone. Thing. The formula I-2 of claim 1

[Where:
R ¹ is halogen;
R ² is halogen, lower alkyl, lower alkoxy, lower alkyl substituted with halogen, lower alkoxy substituted with halogen, or phenyl;
Ar is aryl or heteroaryl;
n is 0, 1 or 2;
m is 0, 1 or 2]
Or a pharmaceutically suitable acid addition salt, optically pure enantiomer, racemate or diastereomeric mixture thereof. {(S) -3-[(6-Fluoro-benzothiazol-2-ylamino) -methyl] -pyrrolidin-1-yl}-(2-trifluoromethyl-phenyl) -methanone {(S) -3- [ (6-Fluoro-benzothiazol-2-ylamino) -methyl] -pyrrolidin-1-yl}-(2-trifluoromethoxy-phenyl) -methanone {(S) -3-[(6-Fluoro-benzothiazole- 2-ylamino) -methyl] -pyrrolidin-1-yl}-[2- (1,1,2,2-tetrafluoro-ethoxy) -phenyl] -methanone {(S) -3-[(6-fluoro- Benzothiazol-2-ylamino) -methyl] -pyrrolidin-1-yl}-(5-methyl-2-trifluoromethyl-phenyl) -methanone {(S) -3-[(6-fluoro- Benzothiazol-2-ylamino) -methyl] -pyrrolidin-1-yl}-(5-methyl-3-phenyl-isoxazol-4-yl) -methanone {(S) -3-[(6-fluoro-benzo Thiazol-2-ylamino) -methyl] -pyrrolidin-1-yl}-(5-phenyl-isoxazol-4-yl) -methanone (2-chloro-5-methyl-phenyl)-{(S) -3- [(6-Fluoro-benzothiazol-2-ylamino) -methyl] -pyrrolidin-1-yl} -methanone or {(S) -3-[(6-Fluoro-benzothiazol-2-ylamino) -methyl]- 6. A compound of formula I-2 according to claim 5, which is pyrrolidin-1-yl}-(2-methoxy-5-methyl-phenyl) -methanone. {(S) -3-[(6-Fluoro-benzothiazol-2-ylamino) -methyl] -pyrrolidin-1-yl}-[2- (1,1,2,2-tetrafluoro-ethoxy) -phenyl ] -Methanone {(S) -3-[(6-Fluoro-benzothiazol-2-ylamino) -methyl] -pyrrolidin-1-yl}-(5-methyl-3-phenyl-isoxazol-4-yl) -Methanone or {(S) -3-[(6-fluoro-benzothiazol-2-ylamino) -methyl] -pyrrolidin-1-yl}-(5-phenyl-isoxazol-4-yl) -methanone 6. A compound of formula I-2 according to claim 5. The formula I-3 according to claim 1.

[Where:
R ¹ is halogen;
R ² is halogen, lower alkyl, lower alkoxy, lower alkyl substituted with halogen, lower alkoxy substituted with halogen, or phenyl;
Ar is aryl or heteroaryl;
n is 0, 1 or 2;
m is 0, 1 or 2]
Or a pharmaceutically suitable acid addition salt, optically pure enantiomer, racemate or diastereomeric mixture thereof. {(S) -3-[(6-Chloro-quinoxalin-2-ylamino) -methyl] -pyrrolidin-1-yl}-(2-trifluoromethoxy-phenyl) -methanone {(S) -3-[( 6-chloro-quinoxalin-2-ylamino) -methyl] -pyrrolidin-1-yl}-[2- (1,1,2,2-tetrafluoro-ethoxy) -phenyl] -methanone {(S) -3- [(6-Chloro-quinoxalin-2-ylamino) -methyl] -pyrrolidin-1-yl}-(5-methyl-2-trifluoromethyl-phenyl) -methanone {(S) -3-[(6-chloro -Quinoxalin-2-ylamino) -methyl] -pyrrolidin-1-yl}-(5-methyl-3-phenyl-isoxazol-4-yl) -methanone {(S) -3-[(6-chloro-quinoki Salin-2-ylamino) -methyl] -pyrrolidin-1-yl}-(5-phenyl-isoxazol-4-yl) -methanone (2-chloro-5-methyl-phenyl)-{(S) -3- [(6-Chloro-quinoxalin-2-ylamino) -methyl] -pyrrolidin-1-yl} -methanone or {(S) -3-[(6-Chloro-quinoxalin-2-ylamino) -methyl] -pyrrolidine- 9. A compound of formula I-3 (n is 1) according to claim 8, which is 1-yl}-(2-methoxy-5-methyl-phenyl) -methanone.   {(S) -3-[(6-Chloro-quinoxalin-2-ylamino) -methyl] -pyrrolidin-1-yl}-[2- (1,1,2,2-tetrafluoro-ethoxy) -phenyl] A compound of formula I-3 according to claim 8, which is -methanone. R ¹ is Cl or F, a compound according to any of claims 1, 2, 5 or 8.   12. A compound according to any one of claims 1, 2, 5, 8 or 11 wherein n is 1. R ² is lower alkyl, lower alkoxy, lower alkoxy substituted by halogen, or phenyl, A compound according to any one of claims 1,2,5,8,11 or 12. R ² is methyl, methoxy, 1,1,2,2-tetrafluoro - ethoxy or phenyl, Compounds according to any of claims 1,2,5,8,11,12 or 13.   15. A compound according to any one of claims 1, 2, 5, 8, 11, 12, 13 or 14 wherein m is 1 or 2.   16. A compound according to any one of claims 1, 2, 5, 8, 11, 12, 13, 14 or 15 wherein Ar is phenyl or isoxazolyl. a) Formula

A compound represented by the formula

Is reacted with a compound represented by the formula:

(Wherein R ¹ , R ² , Ar, hetaryl, m and n are defined in any one of claims 1 to 16),
And, if necessary, preparing a compound of formula I as defined in any of claims 1 to 16, comprising converting the resulting compound to a pharmaceutically acceptable acid addition salt Way for.   18. A compound of formula I according to claim 1 prepared by the method of claim 17 or an equivalent method.   A medicament comprising one or more compounds of formula I as defined in any of claims 1 to 16 and a pharmaceutically acceptable excipient. Sleep apnea, narcolepsy, insomnia, sleep-related complications, jet lag syndrome, circadian rhythm disorders, restless leg syndrome, sleep disorders, anxiety, depression, manic depression, obsessive compulsive disorder, affective neuropathy , Depressive neurosis, anxiety, mood disorder, delirium, panic attack disorder, post-traumatic stress disorder, sexual dysfunction, schizophrenia, psychosis, cognitive impairment, Alzheimer's and Parkinson's disease, dementia, mental retardation, dyskinesias including Huntington's disease and Tourette's syndrome, 嗜 habit, craving associated with drug abuse, including seizure disorders, epilepsy, psychiatric, neurological and neurodegenerative disorders, metabolic disorders, such as obesity, diabetes, appetite Eating disorders including anorexia and bulimia, asthma, migraine, pain, neuropathic pain, sleep disorders related to psychiatric, neurological and neurodegenerative disorders, neuropathic Pain, hyperalgesia, causalgia, and enhance or deterioration of sensitivity to pain, including allodynia, acute pain, burn pain, back pain, complex regional pain syndrome I and II, arthritic pain, post-stroke 20. A medicament according to claim 19, for the treatment of pain, neuralgia, HIV infection related pain, post-chemotherapy pain or irritable bowel syndrome.   21. The medicament according to claim 20, for the treatment of sleep disorders, wherein the sleep disorder is sleep disorder associated with sleep apnea, narcolepsy, insomnia, parasomnia, jet lag syndrome and neuropsychiatric disorders. . Sleep apnea, narcolepsy, insomnia, sleep-related complications, jet lag syndrome, circadian rhythm disorders, restless leg syndrome, sleep disorders, anxiety, depression, manic depression, obsessive compulsive disorder, affective neuropathy , Depressive neurosis, anxiety, mood disorder, delirium, panic attack disorder, post-traumatic stress disorder, sexual dysfunction, schizophrenia, psychosis, cognitive impairment, Alzheimer's and Parkinson's disease, dementia, mental retardation, dyskinesias including Huntington's disease and Tourette's syndrome, 嗜 habit, craving associated with drug abuse, including seizure disorders, epilepsy, psychiatric, neurological and neurodegenerative disorders, metabolic disorders, such as obesity, diabetes, appetite Eating disorders including anorexia and bulimia, asthma, migraine, pain, neuropathic pain, sleep disorders related to psychiatric, neurological and neurodegenerative disorders, neuropathic Pain, hyperalgesia, causalgia, and enhance or deterioration of sensitivity to pain, including allodynia, acute pain, burn pain, back pain, complex regional pain syndrome I and II, arthritic pain, post-stroke Use of a compound of formula I according to any of claims 1 to 16 for the preparation of a medicament for the treatment of pain, neuralgia, HIV infection related pain, post-chemotherapy pain or irritable bowel syndrome.   The sleep disorder is a sleep disorder associated with sleep apnea, narcolepsy, insomnia, sleep parasomnia, jet lag syndrome, circadian rhythm disorder or neurological disorder, as shown in Formula I of claim 22 Use of compounds.